MEK inhibition enhances presentation of targetable MHC-I tumor antigens in mutant melanomas

Combining multiple therapeutic strategies in NRAS/BRAF mutant melanoma, namely MEK/BRAF kinase inhibitors, immune checkpoint inhibitors, and targeted immunotherapies, may offer an improved survival benefit by overcoming limitations associated with any individual therapy. Still, optimal combination, order, and timing of administration remains under investigation. Here, we measure how MEK inhibition alters anti-tumor immunity by utilizing quantitative immunopeptidomics to profile changes the peptide MHC (pMHC) repertoire. These data reveal a collection of tumor antigens whose presentation levels are selectively augmented following therapy, including several epitopes present at over 1000 copies-per-cell. We leveraged the tunable abundance of MEKi-modulated antigens by targeting 4 epitopes with pMHC-specific T cell engagers and antibody drug conjugates, enhancing cell killing in tumor cells following MEK inhibition. These results highlight drug treatment as a means to enhance immunotherapy efficacy by targeting specific upregulated pMHCs and provide a methodological framework for identifying, quantifying, and therapeutically targeting additional epitopes of interest.

Fusion Oncogenes Are Associated With Increased Metastatic Capacity and Persistent Disease in Pediatric Thyroid Cancers

PURPOSE In 2014, data from a comprehensive multiplatform analysis of 496 adult papillary thyroid cancer samples reported by The Cancer Genome Atlas project suggested that reclassification of thyroid cancer into molecular subtypes, RAS-like and BRAF-like, better reflects clinical behavior than sole reliance on pathologic classification. The aim of this study was to categorize the common oncogenic variants in pediatric differentiated thyroid cancer (DTC) and investigate whether mutation subtype classification correlated with the risk of metastasis and response to initial therapy in pediatric DTC. METHODS Somatic cancer gene panel analysis was completed on DTC from 131 pediatric patients. DTC were categorized into RAS-mutant ( H-K-NRAS), BRAF-mutant ( BRAF p.V600E), and RET/ NTRK fusion ( RET, NTRK1, and NTRK3 fusions) to determine differences between subtype classification in regard to pathologic data (American Joint Committee on Cancer TNM) as well as response to therapy 1 year after initial treatment had been completed. RESULTS Mutation-based subtype categories were significant in most variables, including age at diagnosis, metastatic behavior, and the likelihood of remission at 1 year. Patients with RET/ NTRK fusions were significantly more likely to have advanced lymph node and distant metastasis and less likely to achieve remission at 1 year than patients within RAS- or BRAF-mut subgroups. CONCLUSION Our data support that genetic subtyping of pediatric DTC more accurately reflects clinical behavior than sole reliance on pathologic classification with patients with RET/ NTRK fusions having worse outcomes than those with BRAF-mutant disease. Future trials should consider inclusion of molecular subtype into risk stratification.

Triple-Regimen of Vemurafenib, Irinotecan, and Cetuximab for the Treatment of BRAFV600E-Mutant CRC: A Case Report and Review

Mutation of the BRAF proto-oncogene is found in approximately 10% of colorectal cancers (CRC), with much of the mutation conferred by a V600E mutation. Unlike other CRC subtypes, BRAF-mutant CRC have had relatively limited response to conventional therapies and overall poor survival. We present the case of a 75-year-old man with severe nonischemic cardiomyopathy on a LifeVest who was found to have a transverse colonic mass with widespread hepatic metastatic disease and was subsequently found to have BRAFV600E-mutant CRC (MSI High/dMMR). After a failed therapy with FOLFOX and pembrolizumab, the patient was started on a regimen of vemurafenib, irinotecan, and cetuximab (VIC) based on the SWOG 1406 trial which had shown improved progression-free survival and response rate for the treatment of BRAFV600E-mutant metastatic CRC. After 40 cycles of VIC, the patient attained complete response and is in remission off chemotherapy with significant improvement. This case highlights the effectiveness of the triple-regimen of vemurafenib, irinotecan, and cetuximab as a treatment option for BRAFV600E-mutant CRC, which is a treatment regimen based on the SWOG 1406 trial, and also demonstrates the synergistic role of BRAFV600E inhibitors and EGFR inhibitors in the treatment of BRAFV600E-mutant CRC.

BRAF-mutant melanoma of the skin during pregnancy with dichorionic diamniotic twins. Clinical case

Per the majority of authors, melanoma is the most common tumor diagnosed during pregnancy (31 % of all malignant neoplasms). In approximately 1/3 of women melanoma developed in child-bearing age is diagnosed during pregnancy or in the postpartum period. However, only some retrospective studies analyzed the effect of pregnancy on melanoma development, and conclusive data on development, progression and treatment of BRAF-mutant melanoma is lacking. In this subpopulation of patients, BRAF status supposedly can negatively affect disease outcome irrespective of treatment methods.The article presents a clinical case of recurrence of melanoma with the BRAF V600E mutation during pregnancy. The patient underwent lymph node dissection during pregnancy prolongation, after labor she received antitumor drug therapy with МЕК and ВRAF inhibitors. Melanoma recurrence during pregnancy did not worsen treatment outcomes for the mother and embryo.